This application is in response to Challenge Area 04-HL-104, "Perform secondary analyses of existing data to answer important clinical and preventive medicine research questions." The specific topic is #8, "Analysis of genetic markers related to risk factors and disease in relation to their genetic and environmental context and how these may be used to inform preventive medicine and clinical care. Together, emphysema and chronic obstructive pulmonary disease (COPD) will soon surpass stroke as the third leading cause of death in the United States, with the largest increase occurring in Americans of non-European ancestry. Emphysema is defined by a permanent enlargement of airspaces with destruction of alveolar walls;COPD, by airflow limitation that is not fully reversible. Mutations in the SERPINA1 gene cause panlobular emphysema but account for <1% of cases. Smoking is the major environmental cause centrilobular emphysema, but less than one third of heavy smokers develop either disease, which may suggest a genetic risk. However, no other putatively causal genes have been confirmed for emphysema, in part due to a lack of quantitative measures of emphysema in cohorts with dense genotyping. The Multi-Ethnic Study of Atherosclerosis (MESA) and MESA-Family Studies performed cardiac computed tomography (CT) scans for 6,814 participants age 45-84 years free of clinical cardiovascular disease and 595 families (2077 participants). The MESA-Family Study performed linkage studies for subclinical atherosclerosis, and one million SNP genome wide association study (GWAS) data will be available for both studies. The MESA-Lung Study measured and validated quantitative emphysema phenotypes on the lung regions of cardiac CT scans for 3,965 MESA participants. This sample size, however, is adequate to detect only large associations at GWAS levels of significance. We therefore propose to measure quantitative emphysema phenotypes on cardiac CT scans for the other 2,579 MESA participants and 2,077 MESA Family Study participants. We will then use existing genome- wide linkage and GWAS data among 595 families of African and Hispanic ancestry and 6,544 participants of African, Hispanic, European or Chinese ancestry to conduct statistical genetic analysis of: 1) family-based linkage and GWAS for quantitative emphysema phenotypes in the MESA-Family Study and 2) GWAS analyses for quantitative emphysema phenotypes in the MESA cohort before and after stratification by smoking history. This application proposes to combine data from the MESA, MESA Lung and MESA Family Studies and add selective new data to perform novel, highly cost-effective research on the genetic basis of emphysema among 8,120 participants in a population-based cohort and family study. The proposed research on quantitative emphysema phenotypes is unique in utilizing a cohort rather than case-control design, including non-smokers, and enrolling minority ethnic groups in which the prevalence of the disease in rising most rapidly. The proposed aims will examine the role of DNA variation in the genome and modification by smoking history to identify risk variants and provide insight for future functional and genotype/phenotype research that will disclose disease pathways, and therapeutic targets. Emphysema will soon overtake stroke as the third leading cause of death in the US, with the greatest increase among African-Americans and Asians. Therapeutic options are few, in part due to a limited understand of its causes. Smoking causes some types of emphysema but most smokers do not develop emphysema, which might suggest a genetic risk. This study proposes to measure emphysema on existing CT scans in a large multiethnic cohort and family study (n=8,120) with 1 million SNP genome-wide and linkage data to examine genetic risk for emphysema, which may lead to a better understanding of risk for emphysema.